BORCS6 is involved in the enlargement of lung lamellar bodies in Lrrk2 knockout mice
BORCS6 is involved in the enlargement of lung lamellar bodies in Lrrk2 knockout mice
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DOI：
10.1093/hmg/ddab146
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发表时间：
2021-06-02
影响因子：
3.5
通讯作者：
Tomita, Taisuke
中科院分区：
文献类型：
--
作者：
Araki, Miho;Ito, Kyohei;Tomita, Taisuke
富亮氨酸重复激酶2 （LRRK2）与帕金森病的发病机制有关。研究表明，Lrrk2敲除（KO）的啮齿动物在肺泡上皮II型细胞中具有增大的板层体（LBs），尽管其潜在机制尚不清楚。我们对从Lrrk2 KO小鼠中分离的LB进行了蛋白质组学分析，发现Lrrk2 KO小鼠的LB蛋白质组与野生型小鼠有很大的不同。在Lrrk2 KO LBs中，几种Rab蛋白增加，block -1相关复合物（BORC）亚基蛋白减少。Lrrk2 KO小鼠支气管肺泡灌洗液中表面活性剂蛋白C含量明显降低，提示Lrrk2 KO小鼠LB胞吐功能受损。我们还发现，在LRRK2的KO或用LRRK2抑制剂处理细胞后，A549细胞中LBs的增加也会重现。通过这个模型，我们发现BORC亚基基因BORCS6的KO导致LB增大，而不是其他BORC基因。我们的研究结果提示LRRK2-BORCS6通路参与了LB形态的维持。
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson disease. It has been shown that Lrrk2 knockout (KO) rodents have enlarged lamellar bodies (LBs) in their alveolar epithelial type II cells, although the underlying mechanisms remain unclear. Here we performed proteomic analyses on LBs isolated from Lrrk2 KO mice and found that the LB proteome is substantially different in Lrrk2 KO mice compared with wild-type mice. In Lrrk2 KO LBs, several Rab proteins were increased, and subunit proteins of BLOC-1-related complex (BORC) were decreased. The amount of surfactant protein C was significantly decreased in the bronchoalveolar lavage fluid obtained from Lrrk2 KO mice, suggesting that LB exocytosis is impaired in Lrrk2 KO mice. We also found that the enlargement of LBs is recapitulated in A549 cells upon KO of LRRK2 or by treating cells with LRRK2 inhibitors. Using this model, we show that KO of BORCS6, a BORC subunit gene, but not other BORC genes, causes LB enlargement. Our findings implicate the LRRK2-BORCS6 pathway in the maintenance of LB morphology.